Arrhythmic Effects of Cannabis in Ischemic Heart Disease

Abstract

Rationale:

Cannabis use is increasing worldwide, especially among older individuals at risk for chronic ischemic heart disease (IHD). However, little is known about the arrhythmic effects of cannabis use in IHD. Accordingly, we prospectively assessed the relationship between cannabis use, heart rate (HR), and arrhythmias in healthy age-matched controls and subjects with IHD.

Methods:

Healthy controls (n=37, 57% men) and subjects with IHD (myocardial infarction ≥3 months ago; n=24, 58% men) who used cannabis wore a Zio^® (iRhythm Technologies) monitor for 14 days. Noncannabis using ischemic subjects (n=35, 51% males) wore Zio monitors for standard clinical indications. Baseline HR was compared with average HR measured for 4 h following consumption and changes in HR and frequency of arrhythmias were correlated with cannabis use.

Results:

In controls, HR increased 20 min (4.99±6.7 bpm, p=0.08) after use, then declined 4 h following use (−7.4±7.7, p<0.001). Conversely, subjects with IHD showed minimal HR increase (1.6±3.9 bpm) and blunted HR decline (−3.4±5.6 bpm, p<0.001). Supraventricular tachycardia (SVT) (29.7% vs. 58.3%; p=0.04) and nonsustained ventricular tachycardia (NSVT) (5.6% vs. 47.8%, p=0.01) were the most frequently occurring arrhythmias in controls and IHD subjects, respectively. Incidence of SVT decreased as cannabis use increased in both groups. Conversely, NSVT tended to increase with increased use in controls, and was significantly more prevalent in IHD. However, overall arrhythmia burden did not differ between cannabis users and nonusers with IHD.

Conclusion:

Our findings demonstrate that chronic cannabis use is associated with only mild HR changes, which are blunted in IHD. In addition, our data suggest that among cannabis users, arrhythmias are more frequent in IHD subjects that in healthy subjects.

Introduction

Laws regulating cannabis use are rapidly changing. At present, recreational cannabis use is legal in 18 states and the District of Columbia; it can be prescribed for medicinal use in 36 states, Guam, Puerto Rico and the U.S. Virgin Islands.¹ It is estimated that 8.5 million people in the United States use marijuana daily² and recent federal data reported a stunning increase of 455% in cannabis use among U.S. adults at ages 55–64 years and 333% in those over the age of 64 years.³

Cardiovascular disease is the leading cause of mortality in the United States, accounting for ∼25% of all deaths. The prevalence of cardiovascular disease, including chronic ischemic heart disease (IHD) increases with increasing age, such that nearly 20% of men and 10% of women over the age of 60 years have IHD.⁴ With increased cannabis consumption in older individuals, it is likely that individuals with IHD will be cannabis users and patients with cardiovascular disease are more frequently asking clinicians about the safety of cannabis use. Yet, because the cardiovascular effects are not fully understood, there are no comprehensive guidelines currently in place for safe cannabis use in patients with IHD.⁵

Several reviews have focused on adverse cardiovascular effects of cannabis use^6–8; however, evidenced-based research guiding these reviews is limited. Furthermore, although Mittleman et al. demonstrated a significant increase in the likelihood to suffer a myocardial infarction (MI) in the hour after consuming cannabis,⁹ we recently published a retrospective analysis of over 3 million post-MI hospital admissions examining the short-term outcomes following MI in cannabis users. Consistent with the previous study,⁹ we found a decrease in the average age of onset of MI in people who used cannabis. However, we found a significant decrease in in-hospital mortality in cannabis users.¹⁰

Of interest, in a follow-up study examining the long-term outcomes of the cohort from their 2001 study,⁹ the authors published long-term survival following MI¹¹ and suggested when compared with nonusers, cannabis users had an apparent increase in mortality over 18-year follow-up, although this did not reach statistical significance. It is clear that further research is necessary to better understand current cardiovascular risks of cannabis use.

It is also important to note that there are significant differences between the cannabis products that are being consumed today and those that were historically studied and which formed the foundation of much of our current recommendations. For example, in an early study¹² examining cardiovascular effects of smoked cannabis in 25 male subjects, cannabis use was dose dependently associated with increases in heart rate (HR) with peak HR reached within 30 min after smoking and persisting for more than 90 min.

At an estimated dose of 10 mg tetrahydrocannabinol (THC), subjects demonstrated an increase in HR of ∼40–50 beats per minute, and elevations in systolic and diastolic blood pressure of 10 and 5 mmHg, respectively. It was also reported that 2 of 15 subjects experienced arrhythmias. In this study, subjects were given cannabis cigarettes containing either 0.5% or 2.9% THC. In Colorado, the average THC content of both recreationally and medicinally available cannabis is 18.7%, although concentrates can reach up to 90% THC; only 20 years ago, the average THC content in cannabis was ∼4%.¹³

In a recent meta-analysis¹⁴ of >500,000 arrhythmia hospitalizations, there was a reported 31% increase in arrhythmia admissions in patients with comorbid cannabis use disorder. Similarly, there has been an increase in case reports of arrhythmic cardiac events associated with cannabis use, even in otherwise healthy, younger patients.¹⁵ However, little is known about the risk of arrhythmias in ischemic patients who use cannabis. Accordingly, our objective was to evaluate the effects of cannabis consumption on HR trends and frequency of arrhythmias in healthy controls and ischemic subjects who use cannabis.

Methods

The Colorado Multiple Institutional Review Board for the University of Colorado, Anschutz Medical Campus approved the protocol and participants provided written informed consent. Subjects older than 21 years of age who routinely used cannabis at least twice weekly were eligible. Subjects younger than age 21, older than age 80, were pregnant, or who experienced an MI within the last 3 months were excluded from the study.

Ischemic subjects had either clinically relevant coronary artery disease requiring revascularization or met criteria for MI based on the Expert Consensus Document Universal Definition of MI¹⁶:

• Development of new pathological Q waves with or without symptoms;

• Imaging evidence of region of loss of viable myocardium in absence of nonischemic cause; and

• Pathological findings of a healed or healing MI.

Healthy controls and subjects with IHD wore a Zio^® (iRhythm Technologies) monitor and were instructed to trigger the monitor with each cannabis use for a 2-week period (controls: n=37, uses=390; IHD: n=24, uses=391). Subjects completed a cannabis use diary while wearing their monitors, providing information on the reason for and method of cannabis use. In accordance with institutional policy, research participants provided their own cannabis, and were not given any instruction regarding dose, time of day of use, frequency of use, or method of consumption. A third cohort was included, consisting of noncannabis using ischemic subjects who wore Zio monitors for standard clinical indications.

Time 0 was defined as time of consumption as indicated by a time stamp created when subjects pressed the alert button on the monitor. The baseline average HR was calculated by averaging the mean HR 1 h immediately before use and compared with the average HR, obtained in 20-min intervals, over the next 4 h (Fig. 1). The numerical value of the 20-min interval average HR was determined by digitizing the HR plots using WebPlotDigitizer© (Version 4.2; April, 2019; San Francisco, CA. https://automeris.io/WebPlotDigitizer). Absolute change in HR was determined by subtracting baseline average HR from the average HR for each 20-min interval up to 4 h after use. HR analysis was performed on the first 4 days after enrollment.

FIG. 1.

Representative Zio^® report demonstrating HR quantification parameters. Zio reports were analyzed by quantifying average HR 1 h before use (as denoted by the patient-triggered time stamp) and HR every 20 min for 4 h after use. HR, heart rate.

Automated detection algorithms were used to detect clinically relevant arrhythmias including: supraventricular tachycardia (SVT) (≥4 beats), atrial fibrillation, nonsustained ventricular tachycardia (NSVT) (≥4 beats, <30-s), pauses, AV block (Mobitz second degree and heart block), and burden of premature atrial and ventricular complexes. Arrhythmias were reported as the number of arrhythmic events over the monitoring period. In cannabis-using subjects, we also calculated the frequency of arrhythmias per use as the number of specific arrhythmias captured divided by the number of uses obtained during the monitored period.

Results

Baseline characteristics of the three cohorts are given in Table 1. Controls were younger and less likely to be active tobacco users, but more likely to consume alcohol compared with subjects with IHD. The control population was healthy, without cardiac comorbidities, and were not taking cardiac medications. There were no statistical differences in baseline characteristics between the two ischemic cohorts (cannabis users vs. no-cannabis users).

Table 1.

Baseline Characteristics

Variables	Healthy control cannabis users (n=37)	Ischemic non-cannabis users (n=35)	Ischemic cannabis users (n=24)
Demographics
Mean age (years)	39±14*	59±13	55±9
Race (% White)	83.8	85.7	79.2
Sex (% male)	56.8	51.4	58.3
Active tobacco use (%)	5.4†,‡	14.3	29.2
Alcohol use (%)	78.4†,‡	42.9	58.3
Comorbidities
MI (%)	n/a	85.7	95.8
LVEF (%±standard deviation)	n/a	54.1±11.6	53.3±15.4
Wall motion abnormalities	n/a	54.3	66.7
DM (%)	n/a	25.7	25.0
Hypertension (%)	10.8*	82.9	91.7
Hyperlipidemia (%)	n/a	85.7	83.3
Medications
Aspirin	n/a	91.4	100.0
Clopidogrel/ticagralor	n/a	37.1	41.7
Statin	n/a	91.4	95.8
B-Blocker	n/a	74.3	83.3
Antiarrhythmics	n/a	8.6	8.3

^* p<0.001 Healthy controls versus both ischemic groups.

^† p≤0.03 Healthy controls versus Ischemic cannabis users.

^‡ p≤0.001 Health controls versus ischemic noncannabis users.

DM, diabetes mellitus; LVEF, left ventricular ejection fraction; MI, myocardial infarction.

Smoking was the most common method of cannabis consumption in both controls and IHD subjects (53.5% vs. 55.9%). The most frequently reported reason for use was medicinal (56.9%) in IHD subjects versus recreational (66.3%) in control subjects. In both control and IHD subjects, the majority of uses were reported to be a similar dose of either one puff of high THC (>15%) cannabis or 2–3 puffs of low THC (<15%) cannabis (54.8% vs. 46.82%). On average, controls consumed cannabis 3 times per day compared with four times per day in the IHD cohort (3.1±2.1 vs. 4.2±2.9; p=0.001, respectively).

In general, there was an overall decline in HR following cannabis use as given in Figure 2. Compared with baseline values, HR of controls tended to increase within the first 20 min of consumption (5.0±6.7 bpm; p=0.075), then decreased linearly over the next 4 h (statistically significant reduction compared with baseline values between 80 and 240 min, p≤0.001). In contrast, subjects with IHD experienced little to no increase in HR 20 min after consumption (1.6±3.9 bpm, p=NS) compared with baseline; and a blunted decline in HR over the next 4 h (statistically significant reduction versus baseline values between 80 and 240 min, p≤0.010). Changes were unaffected by frequency of use in controls and IHD subjects (Fig. 3A, B); however, time of cannabis use affected HR changes in controls (Fig. 4A, B).

FIG. 2.

Absolute change from baseline HR following cannabis use. Absolute change in HR was determined by subtracting baseline average HR from the average HR for each 20-min interval up to 4 h after use. Healthy control subjects were analyzed in two groups, less than and older than 40 years to minimize variability owing to age.

FIG. 3.

Absolute change from baseline HR based on frequency of daily cannabis use in (a) controls and (b) subjects with IHD. Changes in HR were unaffected by frequency of use in both control (A) and IHD subjects (B). Similar HR trends were observed at all frequencies of cannabis uses per day. IHD, ischemic heart disease.

FIG. 4.

Effect of time of day on HR trends. HRs were significantly higher in control subjects who consumed cannabis in the morning hours compared with HRs after use in afternoon or evening hours (A). However, in subjects with IHD (B), there was no significant effect of time of day of use on HR trends.

The overall prevalence of any arrhythmia was significantly lower in controls compared with IHD subjects who used cannabis (32.4% vs. 75.0%, p=0.001), and noncannabis IHD subjects (32.4% vs. 77.1%, p=0.0001) (Table 2). Within the IHD cohorts, the overall prevalence of any arrhythmia was similar between subjects who consumed cannabis compared with nonusers (75.0% vs. 77.1%, p=0.849).

Table 2.

Incidence of Arrhythmias Per Subject

	Controls (n=37)	Controls ≥40 years (n=15)	Ischemics no cannabis (n=35)	Ischemics+cannabis (n=23)
Any arrhythmia	32.4%	66.7%	77.1%	75.0%
NSVT	5.4%	13.3%	28.6%†	45.8%*
SVT	29.7%	60.0%	65.7%*	58.3%†
Afib	0.0%	0.0%	8.6%	0.0%
PACs	0.0%	0.0%	8.6%	4.2%
PVCs	2.7%	6.7%	22.9%†	16.7%
Pauses	0.0%	0.0%	2.9%	0.0%
HB	0.0%	0.0%	0.0%	0.0%

^* p<0.015 versus controls; ^†p<0.05 versus controls.

HB, heart block; NSVT, nonsustained ventricular tachycardia; PACs, premature atrial contractions; PVCs, premature ventricular contractions; SVT, supraventricular tachycardia.

SVT (29.7% vs. 58.3%; p=0.041) and NSVT (5.4% vs. 45.8%, p=0.01) were the most frequently occurring arrhythmias in cannabis-using controls and IHD subjects, respectively. SVT was significantly increased in ischemic subjects compared with controls, but there was no difference between noncannabis-using ischemic subjects compared with cannabis-consuming ischemic subjects (45.8% vs. 28.6%, p=0.323) (Fig. 5A).

FIG. 5.

Frequency of arrhythmias in cannabis using control and IHD subjects and in IHD subjects who did not use cannabis. The occurrence of both SVT (A) and NSVT (B) was higher in IHD subjects compared with control subjects; however, there were no differences between cannabis-using and nonusing subjects IHD subjects in the frequency of SVT or NSVT. *p<0.05 versus controls. NSVT, nonsustained ventricular tachycardia; SVT, supraventricular tachycardia.

Similarly, NSVT was observed more frequently in subjects with IHD and although there was a trend to increased NSVT in subjects who used cannabis when compared with noncannabis users with IHD (65.7% vs. 58.3%, p=0.557) (Fig. 5B), this was not statistically significant. Atrial fibrillation was only observed in noncannabis-using IHD subjects, but not in IHD subjects who consumed cannabis (8.6% vs. 0.0%, p=0.238). Frequency of premature ventricular complexes (PVCs) were significantly higher in noncannabis-using IHD subjects compared with controls (22.9% vs. 2.7%, p=0.034), but not cannabis-using IHD subjects (22.9% vs. 16.7%, p=0.766).

In both control and IHD subjects, frequency of SVT tended to decrease as cannabis use increased (Fig. 6A). Conversely, the frequency of NSVT tended to be higher in controls with greatest cannabis consumption (i.e., >8 uses per day), but not IHD subjects (Fig. 6B); and was significantly more prevalent in IHD subjects compared with controls (2.6% vs. 0.2%, p=0.013).

FIG. 6.

Frequency of arrhythmias based on frequency of daily cannabis use. In both control and IHD subjects, frequency of SVT tended to decrease as cannabis use increased (A). NSVT was only seen in controls with greatest cannabis consumption (i.e.,>8 uses per day). NSVT decreased with increasing frequency of use in subjects with IHD, until the highest level of consumption (B). *p<0.05 versus controls; ^†p<0.03 versus controls.

Discussion

Recently, there has been increased reports of cannabis use and adverse cardiac outcomes, but nearly all are meta- and/or retrospective analysis. To our knowledge, this is the first study directly assessing the effects of cannabis use in human subjects with IHD. The cohorts studied were frequent users of cannabis, consuming on average three to four times daily. Following use, HR tended to increase within the first 20 min, then decrease linearly over the next 4 h.

These findings conflict with historical studies of healthy cannabis users from the 1970s, which reported dose-dependent increase in HR that peaked at 30 min and persisted over the next 90 min.¹² Of importance, our study enrolled only chronic users of cannabis, which may explain these differences as chronic cannabis use has been associated with blunted physiological effects.¹⁷

In the historic study, all subjects had previously used cannabis but only 24% of the subjects were daily cannabis users. Changes in HR following cannabis use are believed to be mediated by cannabis effects on the autonomic nervous system.¹⁸ By observing HR trends and response to Valsalva maneuver, Benowitz et al. reported increased sympathetic and decreased parasympathetic activity following acute exposure to cannabis.¹⁹ Conversely, they observed a transition to decreased sympathetic and increased parasympathetic activity following repeated exposure. Downregulation of cannabinoid receptors owing to chronic use has also been reported.²⁰

Compared with controls, we noted significant blunting of HR trends in subjects with IHD. Indices of HR variability are reduced following acute MI, with increased sympathetic and decreased parasympathetic activity.^21–24 In patients with chronic IHD, beta blockers improve HR variability by reducing sympathetic and restoring parasympathetic activity, which may explain our findings.^25–27 These HR trends were unaffected by frequency of cannabis use in controls and subjects with IHD.

We observed significantly higher HRs in controls who consumed cannabis in the morning hours compared with HRs after use in afternoon or evening hours. The reason for these findings are unknown, but may relate to the circadian rhythm of the autonomic nervous system.²⁸ Circadian effects of cannabis have not yet been explored in any system; this finding warrants further examination.

The most frequently observed arrhythmias were SVT and NSVT. The prevalence of both SVT and NSVT were significantly higher in subjects with IHD compared with controls regardless of cannabis use. This is not surprising, because it is known that subjects with IHD are at greater risk for arrhythmias.^29,30

Using the 2010–2014 National Inpatient Sample database, Desai et al. assessed the frequency of arrhythmias in hospitalized cannabis users.³¹ The prevalence of arrhythmias in hospitalized cannabis users was 2.7%. Atrial fibrillation was the most frequently observed arrhythmia (1.9%), followed by ventricular tachycardia (0.5%). Cannabis users who experienced arrhythmias tended to be older and men. This study did not take into consideration admission diagnosis or patient comorbidities, which likely contribute to differences in type and frequency of arrhythmias observed in our study.

Of interest, we observed a decrease in frequency of SVT as cannabis consumption increased. The lowest incidence was observed in subjects who consumed cannabis >8 times in a 24-h period. Conversely, the prevalence of NSVT seemed to increase as cannabis use increased in controls and was relatively unaffected in subjects with IHD. NSVT tended to decrease in IHD as cannabis increased from <3 uses per day to 6–8 per day, but increased when use exceeded eight times per day. Although these trends were statistically insignificant, the overall incidence of NSVT was low and, thus, may not have adequate power to assess a difference based on frequency of cannabis use.

The cardiac effects of cannabis use, specifically association with acute MI and risk for ventricular arrhythmias is complex and incompletely understood. We¹⁰ and others⁹ previously examined the associations between cannabis use and the incidence of MI. We reported that the mean age of MI was on average 10 years younger in cannabis users compared with nonusers. However, in our previous report, the incidence of cardiac arrest owing to ventricular tachycardia or ventricular fibrillation was similar between cannabis users and nonusers.

Finally, it has also been suggested that cannabinoids may have antiarrhythmic properties.^32,33 Using a rodent model of ischemia–reperfusion injury, Krylatov et al. reported a significant reduction in premature ventricular contractions (PVCs) and ventricular fibrillation during coronary artery occlusion and reperfusion following pretreatment with the endocannabinoid, anandamide,³⁴ and suggested these effects may be mediated by activation of CB2 receptors.³²

Anandamide has also been shown to inhibit the Na⁺/Ca²⁺ exchanger current,³⁵ voltage-dependent sodium and L-type calcium channels,³⁶ the transient outward potassium current,³⁷ and activate the ATP-sensitive potassium current through CB-2 receptors.³⁷ This may lead to reduced intracellular calcium loading during ischemic states and may explain the cardioprotective arrhythmic effects of anandamide acutely. Whether these observations extend to chronic IHD is unknown.

Conclusion

In our study, we observed a tendency for HR to increase within the first 20 min following cannabis consumption, followed by a linear decline over the subsequent 4 h. These HR trends are blunted in subjects with IHD who use cannabis and may be influenced by the use of beta-blockers. No statistically relevant difference was observed in the frequency of arrhythmias between cannabis users and nonusers with IHD. The frequency of SVT arrhythmias decreased as cannabis use increased in both healthy and ischemic populations of cannabis users. Conversely, NSVT seemed to increase as cannabis use increased in healthy controls.

These findings highlight our limited knowledge regarding the potential arrhythmic and/or antiarrhythmic effects of cannabis. Further study is necessary to determine the safety of cannabis use in this population.

Study Limitations

Owing to legal restrictions, this was strictly an observational study, lacking the ability to control dose administration, time of use, method of use, or product strain. We relied on the reliability of participants to accurately document use. Concomitant use of other cardioactive substances such as alcohol, tobacco, or illicit drugs was strongly discouraged during cannabis consumption, but lacked direct oversight. By design, our study population were regular cannabis users. Thus, our observed cardiovascular consequences of cannabis use may be blunted as noted previously, and our findings may not be applicable to infrequent cannabis users.

Finally, the ischemic control population (noncannabis users) were given Zio monitors post-MI for standard clinical indications. Thus, the incidence of arrhythmias in this population may have been higher because of selection bias. Nonetheless, our study significantly contributes to the limited understanding of cardiac electrical effects of cannabis.

Abbreviations Used

DM

diabetes mellitus

HB

heart block

HR

heart rate

IHD

ischemic heart disease

LVEF

left ventricular ejection fraction

MI

myocardial infarction

NSVT

nonsustained ventricular tachycardia

SVT

supraventricular tachycardia

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study was supported by funding from NIH/NCATS Colorado CTSA Grant Number UL1 TR002535 and the Colorado Department of Public Health and Environment (CDPHE).

Cite this article as: Gillett L, Johnson-Sasso C, Miller B, Shakowski C, Walker LA, Tompkins C (2023) Arrhythmic effects of cannabis in ischemic heart disease, Cannabis and Cannabinoid Research 8:5, 867–876, DOI: 10.1089/can.2021.0188.